Transplantation is the preferred method of treatment for many forms of end-stage organ failure. Current therapy in clinical transplantation relies on potent non-specific immunosuppressive drugs to inhibit rejection. While short-term results have improved, long-term outcomes remain inadequate. Furthermore, patients must adhere to life-long treatment regimens that dramatically increase the risks of cardiovascular disease, infections and malignancies. Strategies to promote the acceptance of allogenic tissues without the need for chronic immunosuppression could reduce the risk of these life-threatening complications and expand the application of organ, tissue and cellular transplantation. The goal of this Program Project is to develop and optimize tolerance induction protocols that are efficacious, safe, and clinically applicable. This program will be comprised of three inter-related projects designed to induce tolerance to islet and renal allografts in non-human primates. Project I will explore the ability of anti- CD45RB alone and in combination with a deoxyspergualin analogue and/or sirolimus to induce tolerance based on immunoregulatory mechanisms to renal allografts in cynomolgus monkeys. Project II, will test strategies using costimulation blockade or anti-CD45RB in combination with portal vein donor specific transfusion (DST) in islet cell and renal allograft models in rhesus macaques. Finally, Project ll will explore strategies utilizing combined CD28/CD40 pathway blockade, sirolimus, non-ablative conditioning with busulfan, and bone marrow transplantation to induce stable long-term hematopoietic chimerism and transplantation tolerance to renal allografts in the rhesus macaques. A major concern about tolerance induction is the potential to impair protective immunity. Accordingly, we will also explore the effect of transplantation tolerance induction on memory responses to viral antigens. This project will incorporate knowledge and strategies on the effectiveness of costimulation blockade, anti-CD45RB mAb, cell infusion via the portal vein and small molecule immunosuppressive agents for the control of the existing T cell repertoire as these are potential critical components of a chimerism induction protocol. Therefore in an integrated fashion these projects will investigate two general strategies (immune modulation and chimerism induction) to induce transplantation tolerance to allografts in preclinical non- human primate models.